Potential roles of NCAM/PSA-NCAM proteins in depression and the mechanism of action of antidepressant drugs

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Review

Potential roles of NCAM/PSA-NCAM proteins in depression and the mechanism of action

of antidepressant drugs

Krzysztof Wêdzony, Agnieszka Chocyk, Marzena Maækowiak

Laboratory of Pharmacology and Brain Biostructure, Department of Pharmacologcy, Institute of Pharmacology, Polish Academy of Sciences, Smêtna 12, PL 31-343 Kraków, Poland

Correspondence: Krzysztof Wêdzony, e-mail: wedzony@if-pan.krakow.pl

Abstract:

Recently, it has been proposed that abnormalities in neuronal structural plasticity may underlie the pathogenesis of major depression, resulting in changes in the volume of specific brain regions, including the hippocampus (HIP), the prefrontal cortex (PC), and the amygdala (AMY), as well as the morphology of individual neurons in these brain regions. In the present survey, we compile the data regarding the involvement of the neural cell adhesion molecule (NCAM) protein and its polysialylated form (PSA-NCAM) in the pathogenesis of depression and the mechanism of action of antidepressant drugs (ADDs). Elevated expression of PSA-NCAM may reflect neuroplastic changes, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dynamic changes in synaptic structure. Special emphasis is placed on the clinical data, genetic models, and the effects of ADDs on NCAM/PSA-NCAM expression in the brain regions in which these proteins are constitutively expressed and neurogenesis is not a major factor; this emphasis is necessary to prevent cell proliferation and neurogenesis from obscuring the issue of brain plasticity.

Key words:

antidepressant drugs, depression, NCAM, PSA-NCAM

Abbreviations: ADD – antidepressant drug, ADDs – antide- pressants, antidepressant drugs, AMY – amygdala, FGFR – fibroblast growth factor receptor, FLU – fluoxetine, HIP – hippocampus, NCAM – neural cell adhesion molecule, PC – prefrontal cortex, PSA – 2,8-polysialic acid, PSA-NCAM – polysialylated form of neural cell adhesion molecule, SPT sucrose preference test, TST – tail suspension test

Introduction

The monoaminergic hypothesis that antidepressants (ADDs) act via inhibition of monoamine uptake has been called into question [30]. First, the pharmacol-

ogical effect of these drugs, i.e., the blockade of serotonin and noradrenaline uptake, is not clearly associated with their clinical efficacy [30]. Moreover, the novel antidepressant (ADD) tianeptine is actually a serotonin reuptake enhancer [32]. In addition, the direct, rapid effect of ADDs on monoamines contrasts with the delayed onset of effectiveness of ADDs in the clinic [30]. Recent theories on the pathogenesis of major depression suggest that changes in neuronal plasticity may be responsible for the appearance of depressive symptoms and that ADDs alleviate symptoms by interfering with the mechanism responsible for plasticity of neuronal morphology [36]. These changes may reflect alterations in neuronal structure,

Pharmacological Reports 2013, 65, 14711478 ISSN 1734-1140

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[35, 36] induces dendritic atrophy and reductions in spine density in principal neurons of the hippocampus (HIP) [31] and the medial prefrontal cortex (PC) [40].

Although it is not known whether prolonged stress is sufficient to evoke depression, it is often considered as a precipitating factor for depression in humans.

Nevertheless, when chronic stress models are used with an understanding of the limitations, they can provide powerful information about the underlying mo- lecular and cellular determinants of anatomical alterations in neuronal circuitry, which controls complex stress-related behaviors [36]. Certain types of prolonged stress, such as learned helplessness and chronic mild unpredicted stress, are accepted as realistic depression models [36]. These models indicate that it is not the stress per se but rather an inability to cope with stress that leads to depression [11]. Thus far, there are limited studies with data indicating that there is a reduction in neuronal size, spine density, or synapse density in realistic models of depression (chronic mild stress, learned helplessness) [2, 33].

In the last decade, an impressive body of clinical data has been collected using imaging techniques to examine the morphological and metabolic brain changes that are characteristic of depression [3, 10, 24]. Meta analyses (essential for reviewing findings from different studies and comparing results in a stan- dardized fashion) investigating the changes in voxel- based morphometry have lead to the conclusion that, in the course of depression, there are significant decreases in morphological volume within the cortico- limbic circuit, including the amygdala (AMY), the fronto-medial cortex, the paracingulate cortex, and, depending on the analysis, the HIP [3, 10, 24]. Al- though it is not clear whether the observed changes in human brain volume are causative to depression, they raise an interesting question regarding the cause and effect between plasticity and depression. Shrinkage of the brain structure, as well as the size of individual neurons, is also observed in chronically stressed animals [31, 40]. In the present article, we focus our at- tention on the superfamily of adhesion molecules, which are proteins located on the cell surface that are involved in binding with other cells or with the extracellular matrix in a process called cell adhesion. Spe- cifically, we consider the neural cell adhesion molecule (NCAM) and its polysialylated form (PSA-

to each other and their surroundings. NCAM is a member of the immunoglobulin (Ig) superfamily of adhesion molecules, which are encoded by a single gene. The process of alternative splicing can yield two transmembrane NCAM isoforms – one 180- or 140-kDa isoform – or one 120-kD glucophosphatidyl inositol-linked isoform. The extracellular domain of NCAM is composed of five Ig-like domains followed by two fibronectin type III (FN3) domains. NCAM exhibits two modes of binding: homophilic and het- erophilic. Homophilic binding consists of linkages to a series of counter-receptors, including tyrosine kinase receptors, such as the fibroblast growth factor receptor (FGFR), the brain-derived neurotrophic factor receptor, and the tropomyosin kinase receptor B. Het- erophilic binding, i.e., linkages to other adhesion molecules and various extracellular NCAMs, is also critical for maintenance of proper neuronal connec- tions. To bind 2,8-polysialic acid (PSA), NCAM at- taches to the negatively charged long chains of PSA, conferring anti-adhesive properties on the molecule.

A high degree of NCAM polysialylation on neuronal processes promotes a variety of developmental events, such as axonal growth and fasciculation, cell migration, initiation of synaptic reorganization, and synaptogenesis. The expression of PSA-NCAM is particularly high in the developing brain, as well as in adults in the brain regions that undergo persistent and sustained synaptic plasticity, such as the hypotha- lamo-neurohypophysial system, the olfactory bulb, the medial prefrontal, piriform and entorhinal corti- ces, the AMY, and the HIP. Thus, alterations in the expression of PSA-NCAM may signify that changes in plasticity are occurring in the adult brain (for exam- ples from our laboratory, see [5, 25–27]). Elevated expression of PSA-NCAM may reflect changes in plasticity, whereas decreased expression implies a rigidification of neuronal morphology and an impedance of dynamic changes in synaptic structure (for a extensive review on NCAM/PSA-NCAM, see [12, 14]).

Clinical data

Clinical evidence regarding the involvement of NCAM proteins in depression and bipolar disorders is

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sparse thus far. The soluble form of NCAM proteins was detected in cerebrospinal fluid for the first time in 1988 by Jorgensen [21] and further replicated by Pol- torak et al. in 1996 [38]. Both reports indicated an increased concentration of the soluble form of NCAM in psychiatric patients suffering from bipolar mood disorder and major depression. Importantly, Poltorak found no effect of medication on NCAM concentration (primarily the 120-kDa isoform) [38]. This ap- parent effect raises the question of disease specificity.

Unfortunately, a similar effect has been observed in patients suffering from schizophrenia [45], suggesting a common effect of schizophrenia and depression on brain plasticity, rather than a disease-specific pathol- ogy marked by apparently abnormal NCAM turnover in the CNS of patients with mood disorders. However, depressed patients exhibited decreased PSA-NCAM expression in the basolateral and basomedial AMY [44], while bipolar patients showed the opposite effect [44], as measured by stereological procedures. These effects have now been reproduced by western blot [28]. Interestingly, studies performed on brains do- nated by the Stanley Neuropathology Consortium, which includes controls, schizophrenia, bipolar and major depression patients, no changes in PSA-NCAM expression were observed in PC tissue of bipolar and depressed patients [15].

NCAM gene knockout as a model of depression

The transgenic animal model knocking out the gene encoding the NCAM proteins is a useful tool to verify its role as a potential cause of depression. Mice lack- ing all three major isoforms of NCAM (NCAM–/–) exhibit citalopram- and amitriptyline-sensitive anhedonia measured by the sucrose preference test (SPT) [1]. In the tail suspension test (TST), an assessment designed test invented to screen for the ADDs activ- ity, NCAM–/– animals exhibit an increased time of immobility in comparison to their respective controls.

The above effect has been blocked/attenuated by the classic ADDs amitriptyline and citalopram [22].

These findings indicate that a lack of NCAM proteins is sufficient to evoke “depressive-like” behavior, but is not sufficient to influence the therapeutic effect of ADDs [22]. The effect of NCAM knockout in the TST and SPT has also been reversed by a 15-amino

acid-long peptide, called FGL. The FGL peptide mim- ics the interaction of NCAM with fibroblast growth factor receptors (FGFR), suggesting a novel therapeutic target for drugs aimed at treatment of depression [22]. Although the cognitive impairments observed in the NCAM–/– model may be regarded as models of indecisiveness which accomplishes depression, on one hand, on the other hand, they could interfere with animals’ performance on test assessments evaluating their depressive state. This confound has been re- solved using NCAM +/– heterozygous mice [23].

Again, such NCAM +/– animals display depressive-like symptoms in the TST, the SPT, and the novelty-suppressed feeding test; however, NCAM +/–

mice are devoid of cognitive impairments [23]. It is worth noting here that NCAM–/– animals has exhibit an increased level of fear and anxiety [22], which is observed in the course of depression, and their reduced ability to cope with stress what may result again in their depressive vulnerability [1].

Impact of ADDs on expression of NCAM/PSA-NCAM protein

Thus far, we have found five separate articles demonstrating the impact of ADDs on expression of NCAM/PSA-NCAM protein (see Tab. 1 and its references). These studies are based on chronic ADDs administration [fluoxetine (FLU) (four reports) and imipramine (one study) – see Tab. 1 and references there)]. In all the studies mentioned, elevated expression has been noted in both young-adult and adult animals. Such consistent effects have been observed in the PC or its subregions, while decreased expression has been noted in the AMY in adult but not adolescent rats (see Tab. 1 and its references). Animal age is important because constitutive expression of NCAM/

PSA-NCAM is decreased during the life span [12, 14]. An additional 3 separate experiments utilized a stress model, and both the ADD FLU and the novel ADD, agomelatine, were found to influence stress- induced elevation of NCAM/PSA-NCAM. Two studies indicated that stress elevates the expression of NCAM protein in the PC and the HIP, which is blocked by chronic administration of FLU [8, 9]. Agomelatine [39] normalized the stress- and learning-induced de-

NCAM/PSA-NCAM proteins in depression

Krzysztof Wêdzony et al.

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creases in expression of PSA- NCAM observed in the ventral HIP.

Apart from the phenomenological observation that ADDs (predominately FLU) alters the expression of PSA-NCAM proteins, relatively little is known about the mechanism of above effects. Is not clear whether ADDs, or FLU specifically, directly influences PSA- NCAM or NCAM expression or leads to changes in expression via alterations in neurotransmission – for

example, serotonergic transmission. To our knowl- edge, only one study addresses this issue. It has been found that acute administration of ondansetron, a specific antagonist of 5-HT₃ receptors, in an acute dose alleviated the increase in PSA-NCAM induced by chronic FLU administration [43]. This result appears to suggest that FLU alters PSA-NCAM via changes in serotonergic transmission and in a manner that involved 5-HT₃receptors [43].

drug (dosage and treatment)

Fluoxetine, 21 days, 5 mg/kg ip

Young-adult male Wistar rats

Western blot, NCAM Chronic social isolation

PC Reduction of the PSA-NCAM level elevated by stress.

In naive, no effect

[8]

Immuno-cytochemistry, PSA-NCAM

Naive PC, AMY, HIP

Increase in all analysed regions [17]

Fluoxetine, 21 days, 5 mg/kg ip

Western blot Chronic social isolation

HIP Reduction of the PSA-NCAM level elevated by stress.

Alone, inactive

[9]

Fluoxetine, 21 days, 12 mg/kg po

Young and old male Wistar rats

Immuno-cytochemistry, NCAM/PSA-NCAM

Naive AMY, DR, PC

AMY-increased in adolescent but decreased in adult.

No effects in the other brain regions

[19]

Agomelatine, 22 days, 10 mg/kg ip

Adult male Sprague- Dawley rats

Immuno-cytochemistry Spatial memory training with or without predator stress

vHIP Treatment blocked the water maze-induced decrease in PSA-NCAM in both stressed

and non-stressed animals

[7]

Fluoxetine, 14 days, 10 mg/kg, ip

Adult male Sprague- Dawley rats

Immuno-cytochemistry Naive PC, AMY Increased PSA-NCAM expression in PC and decreased in AMY

[44]

Imipramine, acute 30 mg/kg ip

and chronic, 21 days, 15 mg/kg ip

Adult male Wistar rats

Naive PEC, PIC, HIP

Increase only after chronic treatment

[41]

Naive INC, PRC, CC

Increase [43]

The table was developed using data compiled from a Medline search based on the following key words: antidepressant drugs and PSA-NCAM and antidepressant drugs and NCAM. Two articles were omitted because they address the question of proliferation but not neuroplastic changes. Abbreviations: AMY amygdala, CC cingulate cortex, DR dorsal raphe nucleus, HIP hippocampus, INC infralimbic cortex PC

prefrontal cortex, PEC perilimbic cortex, PIC piriform cortex, PRC prelimbic cortex, vHIP ventral hippocampus, ip intraperitoneal route of drug administration po oral administration (per os)

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Finally, it bears mentioning two published articles that utilized the ability of ADDs to induce neuroplastic changes in a manner that is clearly distinct from their ADDs properties [13, 20]. The first study analyzed the impact of on alteration of NCAM expression in the HIP after kainic acid-induced seizure [20], and the second study analyzed the effect of prolonged administration of venlafaxine on alteration of NCAM expression in ischemic stroke [13]. Administration of kainic acid induces seizures and neuronal death largely in CA3 region, followed by a cascade of neuroplastic changes throughout the HIP, including tem- porary activation of neurogenesis, dispersion of gran- ule cells, and reorganization of mossy fibres [20]. All of the above changes have been restored to control levels after administration of citalopram seven days before and 21 days after administration of kainic acid.

It is also not clear whether citalopram directly influences neuroplastic changes or neuroplastic changes are attenuated by a decrease in seizure severity. The mechanism through which ADDs could alter seizure- evoked neuroplasticity is largely unknown. It has been speculated that the effectiveness of ADDs ad- ministered in a course typical for treatment of depression (i.e., chronic administration) is not only due to changes in neurotransmitter concentrations and/or receptor sensitivity but is also due to an improvement in brain plasticity and tissue remodelling [20]. There is one study analyzing the impact of chronic venlafaxine on expression of NCAM proteins in the mouse HIP after cerebral ischemia [13]. The rationale of these experiments is based on the assumption that ischemic brain injury often results in severe neurological dam- age, which may be the basis for the accompanying cognitive impairment and depressive states [13]. It has been observed that venlafaxine in a dose- dependent manner abrogates the ischemia-induced elevation of NCAM proteins in the HIP [13]. It will be of interest to further analyze the above pathway to investigate first, whether ischemic insults in mice lead to depressive symptoms and, secondly, whether acute or prolonged administration of venlafaxine after ischemic insults is also effective against the ischemia-induced elevation of PSA-NCAM. The results of both studies may indicate that ADDs may be used ef- fectively in brain disorders caused by abnormalities in neuroplasticity [13, 20].

In summary, the data indicating a role of NCAM or PSA-NCAM proteins in realistic models of depression are yet to be discovered. The first step in that di-

rection was a study by Bessa at al. [2] demonstrating that chronic mild stress leading to anhedonia (decreased sucrose preference) provoked an increase in the expression of NCAM mRNA in the rat nucleus accumbens. This effect was reversed by chronic administration of FLU and imipramine [2].

NCAM as potential target for new antidepressants

It is difficult to imagine that molecules of extracellular matrix could be targets for novel ADDs. However, drugs that may alter brain structure are of potential interest not only in the case of depression but also in several other disorders associated with either cognition or learning and memory. In the case of NCAM proteins, it may be proposed that inhibitors or activa- tors of the polysialyltransferases ST8SiaII (STX) and ST8SiaIV (PST), selectively involved in polysialylation of the NCAM protein may constitute a potential drug target. As mentioned above, long negatively charged chains of PSA attached to NCAM confer anti-adhesive properties to the molecule and promote reorganization of the mature brain [12, 14]. STX regulates NCAM polysialylation during embryonic, perinatal, and early postnatal development, whereas PST is predominantly active in the postnatal brain [4, 29]. The data indicating that depression results from developmental origin, or traumatic life events STX and PST are the targets of choice. It is not known whether animals with the gene encoding STX or PST knocked out are “depressive” [4, 29]. Thus far, it has been observed that they display specific impairments in spatial memory but not conditioned fear memory in PST knockouts [29]. It has also been found that both STX and PST knockouts exhibit impaired sociability, while only STX exhibits an increased level of aggression and enhanced stress reactivity, as measured by corticosterone levels in response to stress [4]. Alter- natively, alteration in the level of the circulating soluble form of NCAM may be another target. Soluble NCAM is an antagonist of membrane-bound NCAM.

This antagonism can be achieved by either a specific antibody or a compound that influences or detaches the constitutive membrane-bound NCAM. The family of ADAM (a disintegrin and metalloproteinase) proteins is required for NCAM shedding and may consti-

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after peripheral administration supports further re- search of NCAM proteins as targets of novel ADDs [1, 42].

Conclusion

Although the concept that depression and the mechanism of action of ADDs are associated with remodelling of neuronal circuits that are essential for mood and cognition is interesting, it should, however, be suggested cautiously [36]. First, only a limited number of clinically effective ADDs have been tested (Tab. 1). Secondly, limited, if any, studies analyzed the time course of changes in expression of PSA-NCAM/NCAM after ADD treatment, and there- fore, it is not clear whether the described effects are transient or persistent. In the absence of clear clinical data regarding the involvement of NCAMs in the eti- ology of depression, it is conceivable that these proteins may be involved in the mechanism of action of ADDs but not in the origination of depression. Thus far, the most probable explanation for the effect of ADDs is that they alter serotonergic transmission, precipitating brain remodelling [43]. Subsequently, it will be necessary to investigate symptoms of depression in animal models overexpressing the soluble form of NCAM. Such animals are available and display a schizophrenic-like phenotype [37]. However, the common feature of schizophrenia and depression on the level of mood does not rule out depressive symptoms. Finally, it will be important to confirm the effects of both chronic and acute administration of ADDs. The latter suggestion is important in the con- text of experiments performed on C6 glioma cells that indicated that even short exposure of these cells to FLU, such as 6 hours, increased expression of the NCAM protein [6]. NCAM/PSA-NCAM positive cells are present predominately, if not exclusively, in the population of inhibitory interneurons located in the PC, AMY, and HIP. PSA-NCAM-expressing cells constitute around 10% of the GAD67-expressing interneurons, i.e., GABAergic inhibitory interneurons [16, 34]. Many of the PSA-NCAM-expressing somata are positive for calbindin and somatostatin, and a very

in the neurophil co-expressed markers of GABAergic terminals and neurotransmission, such as the vesicular GABA transporter (VGAT) or GAD67, but virtually none of them expressed the vesicular glutamate transporter 1 (VGLUT1), a marker of glutamatergic neurons [16, 34]. The above characteristics are given here because they provide important information regarding the potential mechanism of action of ADDs. It is con- ceivable that via alteration in structural plasticity gov- erned by PSA-NCAM, ADDs may shift the balance between inhibitory input and excitatory output in neuronal circuits associated with depression.

Acknowledgment:

This work was supported by grant no. POIG.01.01.02.-12-004/09

Depression-Mechanism-Therapy (part 2.2. to MM).

References:

1.Aonurm-Helm A, Jurgenson M, Zharkovsky T, Sonn K, Berezin V, Bock E, Zharkovsky A: Depression-like behaviour in neural cell adhesion molecule (NCAM)-deficient mice and its reversal by an NCAM-derived peptide, FGL. Eur J Neurosci, 2008, 28, 1618–1628.

2.Bessa JM, Morais M, Marques F, Pinto L, Palha JA, Almeida OF, Sousa N: Stress-induced anhedonia is associated with hypertrophy of medium spiny neurons of the nucleus accumbens. Transl Psychiatry, 2013, 3, 1–7.

3.Bora E, Fornito A, Pantelis C, Yucel M: Gray matter abnormalities in Major Depressive Disorder: a meta- analysis of voxel based morphometry studies. J Affect Disord, 2012, 138, 9–18.

4.Calandreau L, Marquez C, Bisaz R, Fantin M, Sandi C:

Differential impact of polysialyltransferase ST8SiaII and ST8SiaIV knockout on social interaction and aggression.

Genes Brain Behav, 2010, 9, 958–967.

5.Chocyk A, Dudys D, Przyborowska A, Maækowiak M, Wêdzony K: Impact of maternal separation on neural cell adhesion molecules expression in dopaminergic brain regions of juvenile, adolescent and adult rats.

Pharmacol Rep, 2010, 62, 1218–1224.

6.Choi MR, Oh DH, Kim SH, Jung KH, Das ND, Chai YG: Fluoxetine increases the expression of NCAM140 and pCREB in rat C6 glioma cells. Psychia- try Investig, 2012, 9, 180–186.

7.Conboy L, Tanrikut C, Zoladz PR, Campbell AM, Park CR, Gabriel C, Mocaer E at al.: The antidepressant agomelatine blocks the adverse effects of stress on memory and enables spatial learning to rapidly increase neural cell adhesion molecule (NCAM) expression in the

(7)

hippocampus of rats. Int J Neuropsychopharmacol, 2009, 12, 329–341.

8.Djordjevic A, Djordjevic J, Elakovic I, Adzic M, Matic G, Radojcic MB: Effects of fluoxetine on plasticity and apoptosis evoked by chronic stress in rat prefrontal cortex. Eur J Pharmacol, 2012, 693, 37–44.

9.Djordjevic A, Djordjevic J, Elakovic I, Adzic M, Matic G, Radojcic MB: Fluoxetine affects hippocampal plasticity, apoptosis and depressive-like behavior of chronically isolated rats. Prog Neuropsychopharmacol Biol Psychia- try, 2012, 36, 92–100.

10.Du MY, Wu QZ, Yue Q, Li J, Liao Y, Kuang WH, Huang XQ at al.: Voxelwise meta-analysis of gray matter reduction in major depressive disorder. Prog Neuropsycho- pharmacol Biol Psychiatry, 2012, 36, 11–16.

11.Duman CH: Models of depression . Vitam Horm, 2010, 82, 1–21.

12.El MA, Rutishauser U: Use of PSA-NCAM in repair of the central nervous system. Adv Exp Med Biol, 2010, 663, 137–147.

13.Fang S, Yan B, Wang D, Bi X, Zhang Y, He J, Xu H et al.: Chronic effects of venlafaxine on synaptophysin and neuronal cell adhesion molecule in the hippocampus of cerebral ischemic mice. Biochem Cell Biol, 2010, 88, 655–663.

14.Gascon E, Vutskits L, Kiss JZ: Polysialic acid-neural cell adhesion molecule in brain plasticity: from synapses to integration of new neurons. Brain Res Rev, 2007, 56, 101–118.

15.Gilabert-Juan J, Varea E, Guirado R, Blasco-Ibanez JM, Crespo C, Nacher J: Alterations in the expression of PSA-NCAM and synaptic proteins in the dorsolateral prefrontal cortex of psychiatric disorder patients. Neuro- sci Lett, 2012, 530, 97–102.

16.Gómez-Climent MA, Guirado R, Castillo-Gómez E, Varea E, Gutierrez-Mecinas M, Gilabert-Juan J, Garcia- Mompó C et al.: The polysialylated form of the neural cell adhesion molecule (PSA-NCAM) is expressed in a subpopulation of mature cortical interneurons character- ized by reduced structural features and connectivity.

Cereb Cortex, 2011, 21, 1028–1041.

17.Guirado R, Sanchez-Matarredona D, Varea E, Crespo C, Blasco-Ibanez JM, Nacher J: Chronic fluoxetine treatment in middle-aged rats induces changes in the expression of plasticity-related molecules and in neurogenesis.

BMC Neurosci, 2012, 13, 5–13.

18.Hinkle CL, Diestel S, Lieberman J, Maness PF: Metallo- protease-induced ectodomain shedding of neural cell adhesion molecule (NCAM). J Neurobiol, 2006, 66, 1378–1395.

19.Homberg JR, Olivier JD, Blom T, Arentsen T, van Brun- schot, Schipper P, Korte-Bouws G et al.: Fluoxetine ex- erts age-dependent effects on behavior and amygdala neuroplasticity in the rat. PLoS One, 2011, 6, e16646.

20.Jaako K, Aonurm-Helm A, Kalda A, Anier K,

Zharkovsky T, Shastin D, Zharkovsky A: Repeated citalopram administration counteracts kainic acid-induced spreading of PSA-NCAM-immunoreactive cells and loss of reelin in the adult mouse hippocampus. Eur J Pharma- col, 2011, 666, 61–71.

21.Jorgensen OS: Neural cell adhesion molecule (NCAM) and prealbumin in cerebrospinal fluid from depressed patients. Acta Psychiatr Scand Suppl, 1988, 345, 29–37.

22.Jurgenson M, Aonurm-Helm A, Zharkovsky A: Behav- ioral profile of mice with impaired cognition in the elevated plus-maze due to a deficiency in neural cell adhesion molecule. Pharmacol Biochem Behav, 2010, 96, 461–468.

23.Jurgenson M, Aonurm-Helm A, Zharkovsky A: Partial reduction in neural cell adhesion molecule (NCAM) in heterozygous mice induces depression-related behaviour without cognitive impairment. Brain Res, 2012, 1447, 106–118.

24.Lai CH: Gray matter volume in major depressive disorder: a meta-analysis of voxel-based morphometry studies. Psychiatry Res, 2013, 211, 37–46.

25.Maækowiak M, Chocyk A, Dudys D, Wedzony K: Acti- vation of CB1 cannabinoid receptors impairs memory consolidation and hippocampal polysialylated neural cell adhesion molecule expression in contextual fear condi- tioning. Neuroscience, 2009, 158, 1708–1716.

26.Maækowiak M, Dudys D, Chocyk A, Wedzony K:

Repeated risperidone treatment increases the expression of NCAM and PSA-NCAM protein in the rat medial prefrontal cortex. Eur Neuropsychopharmacol, 2009, 19, 125–137.

27.Maækowiak M, Grzegorzewska M, Budziszewska B, Chocyk A, Hess G, Wêdzony K: Cocaine decreases the expression of PSA-NCAM protein and attenuates long- term potentiation via glucocorticoid receptors in the rat dentate gyrus. Eur J Neurosci, 2008, 27, 2928–2937.

28.Maheu ME, Davoli MA, Turecki G, Mechawar N:

Amygdalar expression of proteins associated with neuroplasticity in major depression and suicide. J Psychiatr Res, 2013, 47, 384–390.

29.Markram K, Gerardy-Schahn R, Sandi C: Selective learning and memory impairments in mice deficient for polysialylated NCAM in adulthood. Neuroscience, 2007, 144, 788–796.

30.Massart R, Mongeau R, Lanfumey L: Beyond the monoaminergic hypothesis: neuroplasticity and epige- netic changes in a transgenic mouse model of depression.

Philos Trans R Soc Lond B Biol Sci, 2012, 367, 2485–2494.

31.McEwen BS: Stress and hippocampal plasticity. Annu Rev Neurosci, 1999, 22, 105–122.

32.McEwen BS, Chattarji S, Diamond DM, Jay TM, Reagan LP, Svenningsson P, Fuchs E: The neurobiologi- cal properties of tianeptine (Stablon): from monoamine hypothesis to glutamatergic modulation. Mol Psychiatry, 2010, 15, 237–249.

33.Miettinen R, Hajszan T, Riedel A, Szigeti-Buck K, Leranth C: Estimation of the total number of hippocampal CA1 pyramidal neurons: new methodology applied to helpless rats. J Neurosci Methods, 2012, 205, 130–138.

34.Nacher J, Guirado R, Castillo-Gomez E: Structural plasticity of interneurons in the adult brain: role of

PSA-NCAM and implications for psychiatric disorders.

Neurochem Res, 2013, 38, 1122–1133.

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36.Ota KT, Duman RS: Environmental and pharmacological modulations of cellular plasticity: Role in the patho- physiology and treatment of depression. Neurobiol Dis, 2013, 57, 28–37.

37.Pillai-Nair N, Panicker AK, Rodriguiz RM, Gilmore KL, Demyanenko GP, Huang JZ, Wetsel WC, Maness PF:

Neural cell adhesion molecule-secreting transgenic mice display abnormalities in GABAergic interneurons and alterations in behavior. J Neurosci, 2005, 25, 4659–4671.

38.Poltorak M, Frye MA, Wright R, Hemperly JJ, George MS, Pazzaglia PJ, Jerrels SA et al.: Increased neural cell adhesion molecule in the CSF of patients with mood disorder. J Neurochem, 1996, 66, 1532–1538.

39.Pompili M, Serafini G, Innamorati M, Venturini P, Fusar-Poli P, Sher L, Amore M, Girardi P: Agomelatine, a novel intriguing antidepressant option enhancing neuroplasticity: A critical review. World J Biol Psychiatry, 2013, 14, 412–431.

40.Radley JJ, Morrison JH: Repeated stress and structural plasticity in the brain Ageing Res Rev, 2005, 4, 271–287.

41.Sairanen M, O’Leary OF, Knuuttila JE, Castren E:

Chronic antidepressant treatment selectively increases

factor family: neuromodulation of affective behavior.

Neuron, 2012, 76, 160–174.

43.Varea E, Blasco-Ibanez JM, Gomez-Climent MA, Castillo-Gomez E, Crespo C, Martinez-Guijarro FJ, Nácher J: Chronic fluoxetine treatment increases the expression of PSA-NCAM in the medial prefrontal cortex.

Neuropsychopharmacology, 2007, 32, 803–812.

44.Varea E, Guirado R, Gilabert-Juan J, Marti U, Castillo- Gomez E, Blasco-Ibanez JM, Crespo C, Nacher J:

Expression of PSA-NCAM and synaptic proteins in the amygdala of psychiatric disorder patients. J Psychiatr Res, 2012, 46, 189–197.

45.Vawter MP, Frye MA, Hemperly JJ, VanderPutten DM, Usen N, Doherty P, Saffell JL et al.: Elevated concentration of N-CAM VASE isoforms in schizophrenia. J Psy- chiatr Res, 2000, 34, 25–34.

Received: August 26, 2013; in the revised form: September 18, 2013;

accepted: September 20, 2013.